The insulin-like growth factor-I receptor (IGF-IR) mediates the growth-promoting and differentiative effects of the IGFs, whereas the insulin receptor mediates the metabolic responses to insulin. To determine the signaling pathways involved in these cellular responses to activation of the IGF-IR we have utilized a number of techniques, including (a) site-directed mutagenesis of the IGF-IR, (b) activation of known post-receptor signaling pathways, (c) and analysis of substrate specificity. Substitution of specific tyrosine residue in the C-terminal domain of the IGF-IR abrogates the transforming and tumorigenic capabilities of the IGF-IR as demonstrated in soft agar assays and development of tumor formation in nude mice. These tyrosines are important for the interaction of the IGF-IR with the proto-oncogene Crk-II (an SH2-SH3) domain-containing adapter protein), which is phosphorylated on tyrosine residues by the activated IGF-IR. Crk-II demonstrates a higher affinity for the IGF-IR compared with the insulin receptor, and may therefore, represent a substrate specific for the IGF-IR. Cell proliferation may also be enhanced by inhibition of apoptosis. IGF-I inhibits apoptosis by activating both the Ras/Raf/MAP kinase and the phosphoinositide-3' kinase pathways in differentiated cells. Thus, the ability of the activated IGF-IR to induce cellular proliferation and tumor formation involves the C-terminal domain of the IGF-R and is the result of enhanced post-receptor signaling and inhibition of apoptosis.